figure
posted on 2023-03-30, 23:48 authored by Yaoyu Chen, Yi Shan, Min Lu, Ngoc DeSouza, Zhiru Guo, Ronald Hoffman, Aibin Liang, Shaoguang Li <p>Supplemental Figure 1. Comparison of transduction efficiency of JAK2V617F retrovirus between WT and Alox5-/- donor bone marrow cells. Bone marrow cells from WT or Alox5-/- donor mice were transduced with JAK2V617F retrovirus, and transduced with the same virus again 24 hours later. Prior to injection into recipient mice, the percentages of GFP+ cells were analyzed by FACS. Some cells were cultured for two more days (72 hours after initial viral transduction), and then the percentages of GFP+ cells were analyzed.</p>
Funding
MPN Research Foundation
Leukemia & Lymphoma Society
NIH
History
ARTICLE ABSTRACT
Myeloproliferative neoplasms such as polycythemia vera (PV), which are associated with the JAK mutation V617F, remain incurable despite progress in the use of JAK2 inhibitors for treatment of some of these diseases. In this study, we employed mice that undergo JAK2V617F-induced PV as a tool to explore new candidate targets for therapy. Our investigations focused on the lipid metabolic enzyme arachidonate 5-lipoxygenase (Alox5), which we found to be strongly upregulated by JAK2V617F in hematopoietic cells in vitro and in vivo. Notably, genetic deletion of Alox5 or its inhibition in mice with a bioactive small-molecule inhibitor was sufficient to attenuate PV development. This therapeutic effect was associated with induction of a blockade in cell-cycle progression and also with apoptosis in PV cells. Genetic loss exerted an inhibitory effect on PV-initiating cells. Similarly, Alox5 inhibition was sufficient to suppress colony formation in human JAK2V617F-expressing CD34+ cells. Mechanistic investigations showed that Alox5 inhibition reduced AKT activation and decreased β-catenin expression in JAK2V617F-expressing cells. Together, our results define Alox5 as a key genetic effector of JAK2V617F in driving PV, and they identify this enzyme as a candidate therapeutic target to treat this refractory myeloproliferative neoplasm. Cancer Res; 77(1); 164–74. ©2016 AACR.
